Sirolimus

Mechanism of Action

Inhibits T-cell activation and proliferation and inhibits antibody production that occurs in response to antigenic and cytokine stimulation; inhibits T- cell proliferation by inhibiting progression from the G1 to the S phase of the cell cycle

Lymphangioleiomyomatosis

• Lymphangioleiomyomatosis involves lung tissue infiltration with smooth muscle-like cells that harbor inactivating mutations of the tuberous sclerosis complex (TSC) gene (LAM cells)
• Loss of TSC gene function activates the mTOR signaling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors
• Sirolimus inhibits the activated mTOR pathway and thus the proliferation of LAM cells

Absorption

Bioavailability: 14% (oral solution); 41% (tablet)

Peak Plasma Time: 1-3 hr (oral solution); 1-6 hr (tablet)

Distribution

Protein Bound: 92%

Vd:12 L/kg

Metabolism

CYP3A4

Elimination

Half-Life: 2.5 days

Excretion: feces (91%)

Pharmacogenomics

Rapamycins form complexes with an intracellular immunophillin (FKBP), which bind to a kinase called the mammalian target of rapamycin (mTOR)

Intrinsic rapamycin resistance may be caused by genetic mutations identified for FKBP and mTOR genes

• Kidney Failure

Sirolimus is part of the drug class:

• Selective immunosuppressants

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Using sirolimus with certain medicines may affect each other causing serious side effects.

Sirolimus may affect the way other medicines work, and other medicines may affect how sirolimus works.

Especially tell your doctor if you take:

• a medicine to lower your cholesterol or triglycerides
• cyclosporine (including Gengraf, Neoral, Sandimmune) or tacrolimus (Prograf) or other medicines that suppress the immune system
• an antibiotic
• an antifungal medicine
• a medicine for high blood pressure or heart problems
• an anti-seizure medicine
• medicines used to treat stomach acid, ulcers, or other gastrointestinal problems
• bromocriptine mesylate (Parlodel, Cycloset)
• danazol
• an anti-HIV medicine
• St. John’s Wort

This is not a complete list of sirolimus drug interactions. Ask your doctor or pharmacist for more information.

Before taking sirolimus, tell your doctor if you:

• have liver problems
• have skin cancer or it runs in your family
• have high cholesterol or triglycerides (fat in your blood)
• are pregnant or plan to become pregnant. You must use an effective method of birth control during treatment and for 12 weeks after you stop treatment with sirolimus. Tell your doctor right away if you become pregnant or think you are pregnant while taking sirolimus.
• It is not known whether sirolimus passes into breast milk. You and your doctor should decide if you will take sirolimus or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Using sirolimus with certain medicines may affect each other causing serious side effects.

Tell your doctor if you are pregnant or plan to become pregnant. You must use an effective method of birth control during treatment and for 12 weeks after you stop treatment with sirolimus. Tell your doctor right away if you become pregnant or think you are pregnant while taking sirolimus.

Absorption

Bioavailability

Rapidly but poorly absorbed from the GI tract.1 2 Following oral administration as solution, peak blood concentrations occur in approximately 1 hour in healthy individuals and in about 2 hours in renal transplant recipients.1 2 Systemic availability of oral solution is about 14%.1

Sirolimus tablets are not bioequivalent to the oral solution; bioavailability of tablet is about 27% higher relative to the solution.1

Food

Administration of sirolimus (as oral solution or tablets) with high-fat meal increases mean total exposure by 23–35% compared with fasting; effect of food on peak blood concentration was inconsistent depending on the dosage form evaluated.1

Special Populations

In renal transplant patients >65 years of age, sirolimus trough concentrations were similar to those observed in adults 18–65 years of age.1

Distribution

Extent

Extensively partitioned into formed blood elements (mean blood-to-plasma ratio of sirolimus is 36 in stable renal allograft recipients).1 2

Distributed into milk in animals; not known whether sirolimus distributes into human milk or crosses the placenta.1

Plasma Protein Binding

Approximately 92% (mainly albumin [97%]; also α1-acid glycoprotein and lipoproteins).1

Elimination

Metabolism

Extensively metabolized in the intestinal wall and liver by CYP3A4; also a substrate for P-glycoprotein; 7 major metabolites.1

Present in human whole blood principally as sirolimus; sirolimus contributes >90% of the immunosuppressive activity.1

Elimination Route

Excreted mainly in feces (91%).1

Half-life

Terminal elimination half-life: About 62 hours in stable renal transplant patients.1 2

Special Populations

In patients with mild, moderate, and severe hepatic impairment (Child-Pugh class A, B, and C), AUC is increased by 43, 94, and 189%, respectively; as severity of hepatic impairment increased, steady increases in mean sirolimus elimination half-lives and decreases in mean sirolimus clearance normalized for body weight observed.1

Advise patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of the document.

See FDA-Approved Medication Guide.

Dosage

Patients should be given complete dosage instructions [see FDA-Approved Medication Guide].

Skin Cancer Events

Patients should be told that exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor because of the increased risk for skin cancer [see Warnings and Precautions (5.16)].

Pregnancy Risks

Women of childbearing potential should be informed of the potential risks during pregnancy and told that they should use effective contraception prior to initiation of Sirolimus therapy, during Sirolimus therapy, and for 12 weeks after Sirolimus therapy has been stopped [see Use in Specific Populations (8.1)].

This product's label may have been updated. For current full prescribing information, please visit www.greenstonellc.com.

LAB-0620-8.0

Sirolimus Tablets

What is the most important information I should know about Sirolimus?

Sirolimus can cause serious side effects, including:

1. increased risk of getting infections

2. increased risk of getting certain cancers

3.. Increased risk of getting infections. Serious infections can happen including infections caused by viruses, bacteria, and fungi (yeast). Your doctor may put you on medicine to help prevent some of these infections.

Call your doctor right away if you have symptoms of infection including fever or chills while taking Sirolimus.

4. Increased risk of getting certain cancers. People who take Sirolimus have a higher risk of getting lymphoma, and other cancers, especially skin cancer. Talk with your doctor about your risk for cancer.

Sirolimus has not been shown to be safe and effective in people who have had liver or lung transplants. Serious complications and death may happen in people who take Sirolimus after a liver or lung transplant. You should not take Sirolimus if you have had a liver or lung transplant without talking with your doctor.

See the section "What are the possible side effects of Sirolimus?" for information about other side effects of Sirolimus.

What is Sirolimus?

Sirolimus is a prescription medicine used to prevent rejection (anti-rejection medicine) in people 13 years of age and older who have received a kidney transplant. Rejection is when your body's immune system recognizes the new organ as a "foreign" threat and attacks it.

Sirolimus is used with other medicines called cyclosporine (Gengraf, Neoral, Sandimmune), and corticosteroids. Your doctor will decide:

• if Sirolimus is right for you, and
• how to best use it with cyclosporine and corticosteroids after your transplant.

It is not known if Sirolimus is safe and effective in children under 13 years of age.

Sirolimus is a prescription medicine also used to treat lymphangioleiomyomatosis (LAM). LAM is a rare progressive lung disease that affects predominantly women of childbearing age.

Who should not take Sirolimus?

Do not take Sirolimus if you are allergic to Sirolimus or any of the other ingredients in Sirolimus. See the end of this leaflet for a complete list of ingredients in Sirolimus.

What should I tell my doctor before taking Sirolimus?

Before taking Sirolimus, tell your doctor if you:

• have liver problems
• have skin cancer or it runs in your family
• have high cholesterol or triglycerides (fat in your blood)
• are pregnant or plan to become pregnant. You must use an effective method of birth control during treatment and for 12 weeks after you stop treatment with Sirolimus. Tell your doctor right away if you become pregnant or think you are pregnant while taking Sirolimus
• It is not known whether Sirolimus passes into breast milk. You and your doctor should decide if you will take Sirolimus or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Using Sirolimus with certain medicines may affect each other causing serious side effects.

Sirolimus may affect the way other medicines work, and other medicines may affect how Sirolimus works.

Especially tell your doctor if you take:

• a medicine to lower your cholesterol or triglycerides
• cyclosporine (including Gengraf, Neoral, Sandimmune) or tacrolimus (Prograf) or other medicines that suppress the immune system
• an antibiotic
• an antifungal medicine
• a medicine for high blood pressure or heart problems
• an anti-seizure medicine
• medicines used to treat stomach acid, ulcers, or other gastrointestinal problems
• bromocriptine mesylate (Parlodel, Cycloset)
• danazol
• medicines to treat HIV or hepatitis C
• St. John's Wort

How should I take Sirolimus?

• Read the Instructions for Use that comes with your Sirolimus for information about the right way to take Sirolimus tablets
• Take Sirolimus exactly as your doctor tells you to take it.
• Your doctor will tell you how much Sirolimus to take and when to take it. Do not change your dose of Sirolimus unless your doctor tells you to.
• If you also take cyclosporine (Gengraf, Neoral, Sandimmune), you should take your Sirolimus and cyclosporine about 4 hours apart.
• Do not stop taking Sirolimus or your other anti-rejection medicines unless your doctor tells you to.
• Your doctor will check the levels of Sirolimus in your blood. Your doctor may change your dose of Sirolimus depending on your blood test results.
• Sirolimus is taken by mouth 1 time each day.
• Do not crush, chew, or split Sirolimus tablets. Tell your doctor if you cannot swallow Sirolimus tablets. Your doctor can prescribe Sirolimus as a solution.
• Take each dose of Sirolimus the same way, either with or without food. Food can affect the amount of medicine that gets into your bloodstream. Taking each dose of Sirolimus the same way helps keep your blood levels of Sirolimus more stable. Do not take Sirolimus with grapefruit juice.
• If you have taken more medicine than you were told, contact a doctor or go to the nearest hospital emergency department right away.

What should I avoid while taking Sirolimus?

• Avoid receiving live vaccines while taking Sirolimus. Some vaccines may not work as well while you are taking Sirolimus.
• Limit your time in sunlight and UV light. Cover your skin with clothing and use a sunscreen with a high protection factor because of the increased risk for skin cancer with Sirolimus.

What are the possible side effects of Sirolimus?

Sirolimus may cause serious side effects, including:

• See "What is the most important information I should know about Sirolimus?"
• Serious allergic reactions. Tell your doctor or get medical help right away if you get any of following symptoms of an allergic reaction:
  • swelling of your face, eyes, or mouth
  • trouble breathing or wheezing
  • throat tightness
  • chest pain or tightness
  • feeling dizzy or faint
  • rash or peeling of your skin
• Swelling (edema). Fluid may collect in your hands and feet and in various tissues of your body, including in the sac around your heart or lungs. Call your doctor if you have trouble breathing.
• Poor wound healing. Sirolimus may cause your wounds to heal slowly or not heal well. Tell your doctor if you have any redness or drainage, your wound does not heal, or the wound opens up.
• Increased levels of cholesterol and triglycerides (lipids or fat) in your blood. Your doctor should do blood tests to check your lipids during treatment with Sirolimus. Your doctor may prescribe treatment with diet, exercise, or medicine if your lipid levels are too high. During treatment with Sirolimus, your blood levels of cholesterol and triglycerides may remain high even if you follow your prescribed treatment plan.
• Effects on kidney function. When Sirolimus is taken with cyclosporine (Gengraf, Neoral, Sandimmune), the function of your transplanted kidney may be affected. Your doctor should regularly do tests to check your kidney function while you are taking Sirolimus with cyclosporine (Gengraf, Neoral, Sandimmune).
• Increased protein in your urine. Your doctor may regularly test your urine protein.
• Increased risk for viral infections.
  • Certain viruses can live in your body and cause active infections when your immune system is weak. BK virus can affect how your kidney works and cause your transplanted kidney to fail.
  • A certain virus can cause a rare serious brain infection called Progressive Multifocal Leukoencephalopathy (PML). PML usually causes death or severe disability. Call your doctor right away if you notice any new or worsening medical problems such as:
    • confusion
    • sudden change in thinking, walking, strength on one side of your body
    • other problems that have lasted over several days.
• Lung or breathing problems. This can sometimes lead to death. Tell your doctor if you have a new or worsening cough, shortness of breath, difficulty breathing or any new breathing problems. Your doctor may need to stop Sirolimus or lower your dose.
• Blood clotting problems. When Sirolimus is taken with cyclosporine or tacrolimus, you may develop a blood clotting problem. Tell your doctor if you get any unexplained bleeding or bruising.

The most common side effects of Sirolimus in people with renal transplant include:

• high blood pressure
• pain (including stomach and joint pain)
• diarrhea
• headache
• fever
• urinary tract infection
• low red blood cell count (anemia)
• nausea
• low platelet count (cells that help blood to clot)
• high blood sugar (diabetes)

The most common side effects of Sirolimus in people with LAM include:

• mouth sores
• diarrhea
• stomach pain
• nausea
• sore throat
• acne
• chest pain
• upper respiratory tract infection
• headache
• dizziness
• sore muscles.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Sirolimus. For more information ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Sirolimus?

Sirolimus tablets:

• Store Sirolimus tablets at room temperature between 68°F to 77°F (20°C to 25°C).
• Blister cards and strips:Keep the tablets in the original blister container and use the outer carton to protect blister cards and strips from light.
• Bottles: Keep the bottle of Sirolimus tablets tightly closed.

Do not use Sirolimus after the expiration date, which is located on the blister and carton. The expiration date refers to the last day of that month.

Safely throw away medicine that is out of date or no longer needed.

Keep Sirolimus and all medicines out of the reach of children.

General information about the safe and effective use of Sirolimus.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Sirolimus for a condition for which it was not prescribed. Do not give Sirolimus to other people even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Sirolimus. If you would like more information talk to your doctor. You can ask your pharmacist or doctor for information about Sirolimus that is written for health professionals.

For more information about Sirolimus call 1-800-438-1985.

What are the ingredients in Sirolimus?

Active ingredients: Sirolimus

Inactive ingredients: Sirolimus tablets: sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, carnauba wax, dl-alpha tocopherol, and other ingredients. The 0.5 mg and 2 mg dosage strengths also contain yellow iron (ferric) oxide and brown iron (ferric) oxide.

This product's label may have been updated. For current full prescribing information, please visit www.greenstonellc.com.

For Sirolimus oral tablets:

This Medication Guide has been approved by the U.S. Food and Drug Administration.

LAB-0621-4.0

May 2017

ALWAYS DISPENSE WITH
MEDICATION GUIDE

NDC 59762-1001-1
100 Tablets

GREENSTONE® BRAND

Sirolimus
tablets

0.5 mg
For oral use only
Rx only

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Oral:

Rapamune: 1 mg/mL (60 mL) [contains alcohol, usp]

Tablet, Oral:

Rapamune: 0.5 mg, 1 mg, 2 mg

Generic: 0.5 mg, 1 mg, 2 mg

Administer consistently (either with or without food). Renal transplant: Sirolimus should be taken 4 hours after oral cyclosporine (Neoral or Gengraf).

Solution: Mix (by stirring vigorously) with at least 60 mL of water or orange juice. No other liquids should be used for dilution. Patient should drink diluted solution immediately. The cup should then be refilled with an additional 120 mL of water or orange juice, stirred vigorously, and the patient should drink the contents at once.

Tablet: Do not crush, split, or chew.